聽聞中的耐藥性結核病之全口服治療
資料來源：www.thelancet.com/infection Vol 22 July 2022；財團法人台灣紅絲帶基金會編譯
Mafukidze 牧師（因隱私而改名）在他的小石頭教堂周日禮拜的所有部分中，最喜歡聽的就是唱詩班。所有這些共同發出聲音中的某種東西以一種無法取代的方式使他的心裡感到高興。當他接受了抗藥性肺結核治療後僅 6 週，就在他的耳朵裡出現了高音調的嗡嗡聲，這就是為什麼會讓他充滿了恐懼感——這是他的治療方案中注射藥物所引起的聽力損失之早期跡象。除了死亡和每天注射的極度痛苦之外，更讓他害怕的是生活在一個永遠沉默的世界。 Mafukidze 牧師的故事代表了全世界數以萬計的人繼續接受注射療法來治療耐藥結核病的故事。看到這種常見的副作用在他的生活中造成的破壞，他和他的醫療保健提供者共同加入了全球之鬥爭，以終結這些陳舊且未經證實的藥物在耐藥結核病治療中常規的被使用。
注射療法——包括鏈黴素、阿米卡星、卡那黴素或捲曲黴素(streptomycin, amikacin, kanamycin, or capreomycin)——長期以來一直是治療耐藥結核病的基石。儘管這些藥物導致多達 60% 的接受者出現聽力損失，但這些藥物被視為抗藥性結核菌株的關鍵，既是有效的藥物，也是確保順從治療的一種手段，因為它們是基於由衛生保健專業人員每天施打的。藥物注射也是耐藥結核病患者治療中最難以忍受的部分之一。它們在全球的主導地位仍在繼續——即使支持注射療效的試驗證據非常有限——部分原因是它們可在更短的 9-12 個月的治療方案中使用。直到 2020 年，為耐藥結核病患者提供服務的提供者和計畫可以選擇提供更長的 18-24 個月的治療方案，其中包含拯救生命和保護聽力的藥物貝達喹啉 (bedaquiline)，而不是注射劑或者是更短的 9-12 個月的每天注射方案。結核病治療計畫通常選擇更短（和更便宜）之含注射劑的方案，並且很少考慮病患的偏好或觀點。較短的治療方案是更好的概念被耐藥結核病之社區所接受，但忽略了聽力損失的長期影響，因為它並不是結核病計畫成果登記冊中所需監測或捕獲的成果項目。事實上，甚至在為較短的含注射方案提供證據基礎的試驗中，評估聽力損失的正式聽力學測試並沒有常規地進行。
然而，一個位於南非充滿活力的倡導社區確保了那些耐藥結核病患在耐藥結核病注射療法問題上的聲音被聽到。在防禦結核 (TB Proof) （註1） 發起「不聾不死」宣傳運動之後，南非國家衛生部開始推出一種較短的全口服方案，其中包含貝達喹啉 (bedaquiline) 而不是注射藥物，這是基於持續使用注射方式明顯危害上的大膽選擇。 Norbert Ndjeka 及其同事於《刺胳針傳染病》本期22卷的論文中介紹了這一決定的長期結果——很大程度上是基於傾聽耐藥結核病倖存者的需求。該研究報告了一個全國性耐藥結核病患世代的結果，該世代中有的人接受了由七種藥物組成的 9-12 個月的治療方案，其中包括一種注射劑；另一部份的人則接受了由含貝達喹啉七種藥物組成的 9-12 個月的治療方案而不含注射劑的藥物。
接受含貝達喹啉方案的人在所有治療結果中表現更好。接受含貝達喹啉治療的患者的治療成功率高出 14%（95% CI 8-20；69·5% vs 56·7%）；流失率降低 4%（1-8；6·4% vs 12·4%）；治療期間死亡率風險降低 8%（4-11；17·0% vs 22·4%），儘管在評估治療後結果時這種死亡率差異並未持續存在。不幸的是，作者沒有對兩種不同方案的安全性進行比較，鑑於耐藥結核病治療的高毒性率，這是該論文的主要限制。該研究還受到以下事實的限制：它是觀察性的——儘管作者進行了兩次敏感性分析以控制潛在的偏差——以及排除開始是使用含注射劑的方案但後來改用含貝達喹啉的方案的人。然而，將這些患者包括在內，可能會進一步更支持含貝達喹啉的方案。
這些來自南非的長期療效結果應該最終會停止常規使用注射療法去治療耐藥結核病。事實上，應該立即停止常規使用這些藥物去治療耐藥結核病。必須毫不拖延地實施這一受歡迎的舉措，特別是因為 COVID-19 給注射劑的使用增加了額外的風險，因為日常肌肉注射會導致與醫療保健系統的日常互動。然而，這種相對可接受的全口服治療方案需要做更多的工作來加以改進。 Ndjeka 及其同事在研究中使用的南非方案仍然具有較高的每日服藥負擔、較高的死亡率和較低的治療成功率，低於商定的全球耐藥結核病治療目標（成功率 >75%）。雖然與日常使用注射劑相關的危險使結核病社區明確的要求盡快找到替代方案，包括在隨機對照試驗的範圍之外，但現在必須進一步使用更多嚴格的方法，以完善較短的全口服治療方案。包括 PRACTECAL (NCT02589782) 和 endTB (NCT02754765) 研究在內的幾項關鍵試驗一直在使用嚴格的設計和對照組，堅固地評估各種全口服、較短的治療方案。高品質的研究必須驅動耐藥結核病治療的未來建議。然而，南非的經驗顯示，在制定和實施耐藥結核病治療方案時傾聽受影響社區的聲音至關重要。像 Mafukidze 牧師如此勇敢地努力於再次恢復健康的人，不應該擔心他們的生命會被他們尋求拯救自我的治療所毀掉。
*詹妮佛. 佛林 (Jennifer Furin)，佩特羅斯.伊薩基迪斯 (Petros Isaakidis)
jennifer_furin@hms.harvard.edu
哈佛醫學院全球健康與社會醫學系，波士頓，MA 02115，美國（JF）；南非開普敦無國界醫生組織南部非洲醫療隊 (PI)
www.thelancet.com/infection Vol 22 July 2022
註1：TB Proof 係一組織旨在透過以下方式結束結核病的大流行：
建立宣傳能力、為結核病籌集資源、減少結核病的污名、確保衛生設施之安全、追求健康上之公平。
Being heard on all-oral therapy for resistant tuberculosis
www.thelancet.com/infection Vol 22 July 2022
Of all the parts of the Sunday service in his little stone church, Pastor Mafukidze (name changed for privacy) liked listening to the choir best of all. Something about all those voices raised together delighted his heart in a way nothing else could. Which is why the high-pitched buzzing sound that developed in his ears only 6 weeks into his treatment for drug-resistant tuberculosis—an early sign of the hearing loss caused by the injectable medication that was part of his therapeutic regimen— filled him with a sense of dread. More than dying, more than the excruciating pain of the daily injection, he feared living a world of perpetual silence. Pastor Mafukidze’s story typifies that of tens of thousands of individuals around the world who continue to receive injectable therapy for treatment of drug-resistant tuberculosis. Seeing the devastation this common side-effect caused in his life led him and his health-care providers to join the global fight to end the routine use of these old and unproven agents in the treatment of drug-resistant tuberculosis.
Injectable therapy—including streptomycin, amikacin, kanamycin, or capreomycin—has long been a cornerstone of treatment for drug-resistant tuberculosis. Despite causing hearing loss in as many as 60% of the people who receive them, these medications have been seen as lynchpins in the fight against resistant tuberculosis strains, both as effective drugs and as a means of ensuring adherence to therapy, since they are administered by health-care professionals on a daily basis. Injectable drugs are also one of the parts of drug-resistant tuberculosis treatment that people living with the disease find the most difficult to bear. Their worldwide dominance continues—even with very limited trial evidence to support injectable efficacy—in part fueled by their use in a shorter, 9–12 month regimen. Until 2020, providers and programmes offering services for people living with drug-resistant tuberculosis had the option of either giving a longer 18–24 month regimen that contained the life-saving and hearing-sparing medication bedaquiline instead of the injectable or the shorter 9–12 month injectable regimen daily. Tuberculosis programmes often opted for the shorter (and cheaper) injectable containing regimen and rarely considered the preferences or perspectives of the people who were living with the disease. The concept that a shorter regimen is better was accepted in the drug-resistant tuberculosis community, ignoring the long-term impact of hearing loss, because this was not a programmatic outcome captured or monitored in tuberculosis programme registers. In fact, formal audiology testing to assess for hearing loss was not even routinely performed in the trial that provided the evidence base for the shorter, injectable-containing regimen.
A vibrant advocacy community based in South Africa, however, ensured that the voices of those living with the disease were heard on the issue of injectable therapy for drug-resistant tuberculosis. After the “Not Deaf or Dead” advocacy campaign launched by TB Proof, the South African National Department of Health began rolling out an all-oral shorter regimen that contained bedaquiline instead of the injectable drug, a bold choice based on the obvious harms associated with continued injectable use. The long-term results of this decision—based in large measure on hearing the needs of drug-resistant tuberculosis survivors—are presented in the paper by Norbert Ndjeka and colleagues in this issue of The Lancet Infectious Diseases. The study reports the outcomes of a national cohort of individuals diagnosed with drug-resistant tuberculosis who were treated with a 9–12 month regimen consisting of seven drugs, including an injectable, compared with those who received a 9–12 month regimen consisting of seven drugs in which bedaquiline was given instead of the injectable.
People who received the bedaquiline-containing regimens fared better across all treatment outcomes. Those treated with bedaquiline had a 14% higher rate of treatment success (95% CI 8–20; 69·5% vs 56·7%); a 4% lower rate of loss-to-follow-up (1–8; 6·4% vs 12·4%); and an 8% lower mortality risk during treatment (4–11; 17·0% vs 22·4%), although this mortality difference did not persist when post-treatment outcomes were assessed. Unfortunately, the authors do not present a safety comparison between the two different regimens, a major limitation of the paper given the high rates of toxicity seen with drug-resistant tuberculosis treatment. The study is also limited by the fact that it was observational—although the authors did two sensitivity analyses to control for potential biases—and the fact that people who started on an injectable-containing regimen but were later switched to a bedaquiline-containing regimen were excluded. Including such patients, however, would probably have further favoured the bedaquiline-containing regimen.
These long-term efficacy results from South Africa should finally stop the routine use of injectable therapy for drug-resistant tuberculosis. In fact, routine use of these medications for resistant tuberculosis should be immediately halted. This welcome move must be implemented without delay, especially since COVID-19 adds additional risk to injectable use, given the routine interaction with the health-care system due to the daily intramuscular application. More work, however, needs to be done to improve upon this relatively acceptable, all-oral treatment option. The South Africa regimen used in the study by Ndjeka and colleagues8 still has a high daily pill burden, a high rate of mortality, and a lower rate of treatment success than the agreed-upon global goals (success rates >75%) for the treatment of drug-resistant tuberculosis. And while the dangers associated with the daily use of injectables gave the tuberculosis community a clear mandate to find an alternative as quickly as possible, including outside the bounds of randomised controlled trials, further refining of all-oral shorter regimens must now be done using more exacting methods. Several pivotal trials— including the PRACTECAL (NCT02589782) and endTB (NCT02754765) studies—have been doggedly assessing various all-oral, shorter regimens using rigorous designs and control groups. High-quality studies must drive the future of drug-resistant tuberculosis treatment recommendations. What the South Africa experience shows, however, is that listening to the voices of the affected community in the development and implementation of treatment options for drug-resistant tuberculosis is paramount. People like Pastor Mafukidze, who strive so valiantly to become healthy once again, should not fear their lives will be ruined by the very treatment they seek to save them.
*Jennifer Furin, Petros Isaakidis
jennifer_furin@hms.harvard.edu
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA 02115, USA (JF); Southern Africa Medical Unit, Médecins Sans Frontières, Cape Town, South Africa (PI)
www.thelancet.com/infection Vol 22 July 2022